Mitochondrial dysfunction and oxidative stress are hypothesized to play key roles in Parkinson's disease (PD)), motivating the development of therapies aimed at improving mitochondrial energy metabolism and blocking oxidative stress. Peroxisome-proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1?) fills this niche as a master regulator of mitochondrial biogenesis and antioxidant defenses. In support of a critical role of PGC-1?, dopaminergic (DA) neurons of knockout mice show increased vulnerability to degeneration in response to (MPTP). Pgc-1? and its targeted genes are underexpressed in DA neurons at early pathological stages in PD patients, suggesting a failure of this protective response. Two genetic causes of PD: increased ?- synuclein or loss of Parkin (PRKN) each has been shown to suppress PGC-1? expression. Furthermore, loss of PGC-1? increases vulnerability to ?-synuclein (?Syn) toxicity. Thus,increasing PGC-1? could be neuroprotective. Yet, we and others have found that viral-mediated Pgc-1? overexpression at high levels in the nigrostriatal system causes DA neurons to degenerate and increases their susceptibility to MPTP toxicity. Thus, either too much or too little PGC-1? is detrimental to DA neurons. A method to precisely control PGC-1? expression is essential before this can become a viable therapeutic strategy. We now hypothesize a novel post-translational regulatory mechanism to control PGC-1? protein levels, which arises from two observations. First was our unexpected observation that increasing CMA increases PGC-1? protein levels. Next was the recognition that FBXW7, an E3 ubiquitin ligase that tags PGC-1? for degradation by the ubiquitin proteasome system (UPS), harbors the perfect CMA consensus sequence, ?KFERQ?. These findings led us to hypothesize that CMA degrades FBXW7 and thereby reduces UPS-mediated degradation of PGC-1? protein: ?CMA ? ? FBXW7 ? ? PGC-1? . By contrast, inhibiting CMA should increase FBXW7, which would then ubiquitinate PGC-1? leading to its degradation by the UPS. Interestingly, FBXW7 has been identified as a target of PRKN, with PRKN loss leading to increased FBXW7 levels in Prkn-null mice. Furthermore, FBXW7 levels are increased in the brain of PD patients with PRKN mutations. Based on these and other preliminary data, we hypothesize that PGC-1? is regulated through a novel mechanism involving FBXW7 as a link between CMA and UPS. We have obtained additional preliminary data in support of this hypothesis, and will further test it by studying in vitro the mechanism by which manipulations of CMA alter PGC-1? levels, by testing our hypothesis that FBXW7 is a direct substrate for CMA, and by testing our hypothesis that decreasing FBXW7 levels specifically within dopaminergic neurons will be neuroprotective in vivo against ?Syn toxicity. These studies could significantly advance our understanding of mechanisms regulating PGC-1? activity, validate FBXW7 as a therapeutic target in PD, and demonstrate a novel mechanism for regulation of the UPS through CMA-mediated degradation of an E3 ubiquitin ligase.